a) Field of the Invention
This invention relates to compounds and pharmaceutical compositions useful for treating mammalian cholesteremia.
b) Description of Related Art
The natural thyroid hormones, 3, 3',5-triiodo-L-thyronine (T.sub.3) and L-thyroxine (T.sub.4), are recognized cholesteremics which, due to their potent effects on cardiac function, are not indicated for the therapeutic reduction of plasma cholesterol levels in euthyroid subjects.
Since Harington and Barger, Biochem. J. 21, 169-181 (1927), first reported the structure and synthesis of thyroxine, numerous studies have been conducted to identify and synthesize structural analogs which mimic the activity of the natural hormones. The comprehensive review by E. C. Jorgensen in Hormonal Proteins and Peptides, Li, C. H., Ed., Academic Press, New York, Vol. VI, Chapters 2 and 3, 57-204 (1978) summarizes the intensive efforts to vary the thyroxine substituent pattern to produce thyromimetics, primarily for thyroid replacement therapy.
The structure of thyroxine provides considerable opportunities for varying the substituent pattern: ##STR2##
Using rat anti-goiter assays as a touchstone for activity, Jorgensen (vide supra) surmised that certain basic structural characteristics affected activity, as follows:
a) 3,5-disubstitution by size-limited lipophilic groups enhances activity in the order: I&gt;Br&gt;Me=Cl;
b) 3'-substitution by alkyl groups or halogen atoms generally enhances activity in the order: iPr&gt;I&gt;Et&gt;Br&gt;Me&gt;Cl&gt;F&gt;H;
c) halogen substituents are not essential for activity; and d) 5'-substituents decrease activity.
Koerner et al., also relying on rat anti-goiter assays, suggested that the alanine side chain was not necessary to activity and that the O-ether bridge could be replaced by a thioether or methylene bridge. J. Biol. Chem., 250:16, 6417-6423 (1975).
Focusing on the utility of T.sub.3 and its analogs as cholesterol-lowering agents, Underwood et al. have reported the preparation of thyromimetics, one of which was as active as T.sub.3 on the liver, but had only about 0.1% of the activity of T.sub.3 on the heart. Nature 324, 425-429 (1986). These authors concluded that a diphenyl ether core with 4'-OH and 3,5-halogen substitution was essential for high receptor affinity. Such compounds are presumably the subject matter of European Patent Application 0 18 351, published Jul. 23, 1986, in which a number of thyroxine analogs having diphenyl ether cores and 3'-arylalkyl substituents are disclosed.
Leeson, et al. noted that replacement of the 3'-iodo substituent in T.sub.3 had been limited to halogen, small alkyl, phenyl, nitro, and hydroxyl until their own investigations of twenty-nine novel 3'-derivatives. J. Med. Chem. 31, 37-54 (1988). Again, the compounds all have diphenyl ether cores.
Leeson, et al. have further reported that introduction of specific 3'-arylmethyl groups gives liver-selective, cardiac-sparing thyromimetics. Modifications to the 3,5-substituents, ether oxygen, and L-alanyl side chain were also disclosed. These authors observed that the ether oxygen may be replaced by sulfur or methylene, which maintain the orthogonal arrangement of the diphenyl aromatic rings. J. Med. Chem. 32, 320-336 (1989).
The disclosures of the aforementioned patents and publications are incorporated by reference herein.
Despite the long-felt need and the above-noted extensive research efforts, little progress has been made in the development of thyromimetics which lower serum cholesterol without adverse cardiac effects.